Getting a promising drug ready for clinical trials

Lead Investigator: Professor David Allsop

Institution: Lancaster University

Grant type: Project grant 

Duration: 2 years

Amount: £149,164

Scientific Title: Biodistribution, pharmacokinetic and toxicity studies on a novel retro-inverso peptide inhibitor of beta-amyloid oligomer formation

Why did we fund this project?

Comments from members of our Research Network:

'It is vital that we find medications to halt the disease and I believe this study assists in this search.'

'The researchers have clearly created an innovative model of research which has considerable potential value.'

'Given the progress which the professor has made and the great potential of his research for Alzheimer's disease patients and carers, I feel that he should be given the opportunity to continue his work.'

What do we already know?

During Alzheimer's disease, a protein called amyloid-beta begins to clump together, until it forms large plaques of protein that disrupt normal cell function and cause dementia. It is thought that amyloid-beta is toxic to nerve cells (neurones) even when only a small number of pieces of protein have clumped together, before they have formed larger plaques.

Previously, this research team have developed a chemical that binds to small pieces of amyloid-beta, preventing them from clumping together and being toxic to nerve cells. They showed the benefits of this chemical on protecting nerve cells grown in the lab.

However, this particular chemical is not suitable as a drug, as it can't cross the protective layer called the blood-brain-barrier (this exists to prevent harmful things from passing into the brain). To combat this, the researchers developed a 'passport' for the chemical that, when attached, helps it to enter the brain. 

They then tested this new version in mice with genes that cause amyloid plaques to form in their brains – the drug reduced the number of plaques that formed and the number of small, toxic clumps of amyloid-beta as well.

The drug also reduced other signs of Alzheimer's disease, including inflammation and 'oxidative damage', both thought to be caused by toxic amyloid-beta. Additionally, they also saw an improvement in the number of new brain 'stem cells' grown in an area of the brain associated with memory, suggesting that these were also protected from the harmful effects of amyloid-beta.

However, in these earlier studies, the amount of the chemical that reached the brains of the mice was not measured, and nor was the amount of chemical in the other organs or the toxicity of this drug. These measurements are essential as part of safety assessments of potential drugs before they can progress to clinical trials.

What does this project involve?

This project will perform measurements to better understand how much of this drug reaches the brain and other organs of the mice, and how fast it is absorbed into the brain. This is an essential first step in determining a potential dose that should be later tested in clinical trials.

The drug will also be tested for toxicity using a range of different cells from different organs grown in the lab. This is the first step in checking the safety of the drug before it will be allowed to progress to clinical trials in people.

How will this benefit people with dementia?

It is hoped that this project will get the drug to a position where it will be ready to enter clinical trials in people. Currently there are only limited drug treatments available for Alzheimer's disease and these drugs can temporarily alleviate the symptoms of the disease, but they do not target an underlying cause of the disease, and they do not provide a cure. Hence, there is a great clinical need for the development of new drugs aimed at slowing or halting the progression of Alzheimer's disease.